The present invention relates to indole derivatives, to processes and intermediates for their preparation, to pharmaceutical compositions containing them and to their medicinal use. The active compounds of the present invention are useful in treating obesity and other disorders.
It has been recognised that obesity is a disease process influenced by environmental factors in which the traditional weight loss methods of dieting and exercise need to be supplemented by therapeutic products (S. Parker, xe2x80x9cObesity: Trends and Treatmentsxe2x80x9d, Scrip Repons, PJB Publications Ltd, 1996).
Whether someone is classified as overweight or obese is generally determined on the basis of their body mass index (BMI) which is calculated by dividing body weight (kg) by height squared (m2). Thus, the units of BMI are kg/m2 and it is possible to calculate the BMI range associated with minimum mortality in each decade of life. Overweight is defined as a BMI in the range 25-30 kg/m2, and obesity as a BMJ greater than 30 kg/m2. There are problems with this definition in that it does not take into account the proportion of body mass that is muscle in relation to fat (adipose tissue). To account for this, obesity can also be defined on the basis of body fat content: greater than 25% and 30% in males and females, respectively.
As the BMI increases there is an increased risk of death from a variety of causes that is independent of other risk factors. The most common diseases with obesity are cardiovascular disease (particularly hypertension), diabetes (obesity aggravates the development of diabetes), gall bladder disease (particularly cancer) and diseases of reproduction. Research has shown that even a modest reduction in body weight can correspond to a significant reduction in the risk of developing coronary heart disease.
Compounds marketed as anti-obesity agents include Orlistat (Reductil(copyright)) and Sibutramine. Orlistat (a lipase inhibitor) inhibits fat absorption directly and tends to produce a high incidence of unpleasant (though relatively harmless) side-effects such as diarrhoea Sibutramine (a mixed 5-HT/noradrenaline reuptake inhibitor) can increase blood pressure and heart rate in some patients. The serotonin releaser/reuptake inhibitors fenfluramine (Pondimin(copyright)) and dexfenflurarmine (Redux(trademark)) have been reported to decrease food intake and body weight over a prolonged period (greater than 6 months). However, both products were withdrawn after reports of preliminary evidence of heart valve abnormalities associated with their use. There is therefore a need for the development of a safer anti-obesity agent.
The non-selective 5-HT2C receptor agonists/partial agonists m-chlorophenylpiperazine (mCPP) and trifluoromethylphenylpiperazine (TFWPP) have been shown to reduce food intake in rats (G. A. Kennett and G. Curzon, Psychopharmacol., 1988, 98, 93-100; G. A. Kennett, C. T. Dourish and G. Curzon, Eur. J. Pharmacol., 1987, 141, 429453) and to accelerate the appearance of the behavioural satiety sequence (S J. Kitchener and C. T. Dourish, Psychopharmacol., 1994, 113, 369-377). Recent findings from studies with mCPP in normal human volunteers and obese subjects have also shown decreases in food intake. Thus, a single injection of mCPP decreased food intake in female volunteers (A. E. S. Walsh et al., Psychopharmacol., 1994, 116, 120-122) and decreased the appetite and body weight of obese male and female subjects during subchronic treatment for a 14 day period (P. A. Sargeant et al., Psychopharmacol., 1997, 113, 309-312). The anorectic action of mCPP is absent in 5-HT2C receptor knockout mutant mice (L. H. Tecott et al., Nature, 1995, 374, 542-546) and is antagonised by the 5-HT2C receptor antagonist SB-242084 in rats (G. A. Kennett et al., Neuropharmacol., 1997, 36, 609-620). It seems therefore that mCPP decreases food intake via an agonist action at the 5-HT2C receptor.
Other compounds which have been proposed as 5-HT2C receptor agonists for use in the treatment of obesity include the substituted 1-aminoethyl indoles disclosed in EP-A-0655440. CA-2132887 and CA-2153937 disclose that tricyclic 1-aminoethylpyrrole derivatives and tricyclic 1-aminoethyl pyrazole derivatives bind to 5-HT2C receptors and may be used in the treatment of obesity. WO-A-98/30548 discloses aminoalkylindazole compounds as 5-HT2C agonists for the treatment of CNS diseases and appetite regulation disorders. Substituted 1,2,3,4Tetrahydrocarbazoles have been reported as synthetic trypanocides in J. Med. Chem., 1970, 13, 327 and J. Med. Chem., 1973, 16, 1411. 9-(2-Dialkylaminopropyl)-1,2,3,4-tetrahydrocarbazoles have been disclosed in U.S. Pat. No. 2,687,414 and U.S. Pat. No. 2,541,211. 7-Substituted-9-(2-dialkylaminoethyl)-1,2,3,4-tetrahydrocarbazoles have been disclosed in DE 930988. The pharmacological behaviour of 2,3-polymethyleneindoles has been described in J. Med. Chem., 1964, 69, 2910. Derivatives of polynuclear indoles have been described as antidepressants in J. Med. Chem., 1964, 7, 625. Amino-substituted penthienoindoles with pharmacological properties are disclosed in U.S. Pat. No. 3,142,678. 1,2,3,4-Tetrahydro-cyclopent[b]indoles are disclosed in FR 2242983 and DE 2438413. 4(3-Aminobutyl)-1,2,3,4-tetrahydrocyclopent[b]indole has been described in Khim. Geterotskikl. Soedin, 1970, 6,371.
It is an object of this invention to provide selective, directly acting 5HT2 receptor ligands for use in therapy and particularly for use as anti-obesity agents. It is a further object of this invention to provide directly acting ligands selective for 5-HT2B and/or 5-HT2C receptors, for use in therapy and particularly for use as anti-obesity agents. It is a further object of this invention to provide selective, directly acting 5-HT2C receptor ligands, preferably 5-HT2C receptor agonists, for use in therapy and particularly for use as anti-obesity agents.
According to the present invention there is provided a chemical compound of formula (I): 
wherein:
R1 and R2 are independently selected from hydrogen and alkyl;
R3 is alkyl;
R4, R6 and R7 are independently selected from hydrogen, halogen, hydroxy, alkyl, aryl, amino, alkylamino, dialkylamino, alkoxy, aryloxy, alkylthio, alkylsulfoxyl, alkylsulfonyl, nitro, carbonitrile, carbo-alkoxy, carbo-aryloxy and carboxyl;
R5 is selected from hydrogen, halogen, hydroxy, alkyl, aryl, amino, alkylamino, dialkylamino, alkoxy, aryloxy, alkylthio, alkylsulfoxyl, alkylsulfonyl, nitro, carbonitrile, carbo-alkoxy, carbo-aryloxy and carboxyl; and
A is a 5- or 6-membered partially unsaturated or aromatic heterocyclic ring or a 5- or 6-membered partially unsaturated carbocyclic ring,
wherein if A is a 6-membered partially unsaturated carbocyclic ring then at least one of R4 to R7 is other than hydrogen,
and pharmaceutically acceptable salts, addition compounds and prodrugs thereof.
As used herein, the term xe2x80x9calkylxe2x80x9d means a branched or unbranched, cyclic or acyclic, saturated or unsaturated (e.g. alkenyl or alkynyl) hydrocarbyl radical. Where cyclic, the alkyl group is preferably C3 to C12, more preferably C5 to C10. Where acyclic, the alkyl group is preferably C1 to C10, more preferably C1 to C6, more preferably methyl ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, isobutyl or tertiary-butyl) or pentyl (including n-pentyl and iso-pentyl), more preferably methyl. It will be appreciated therefore that the term xe2x80x9calkylxe2x80x9d as used herein includes alkyl (branched or unbranched), alkenyl (branched or unbranched), alkynyl (branched or unbranched), cycloalkyl cycloalkenyl and cycloalkynyl.
As used herein, the term xe2x80x9clower alkylxe2x80x9d means a branched or unbranched, cyclic or acyclic, saturated or unsaturated (e.g alkenyl or alkynyl) hydrocarbyl radical, wherein a cyclic lower alkyl group is C5, C6 or C7, and wherein an acyclic lower alkyl group is methyl, ethyl, propyl (n-propyl or isopropyl) or butyl (n-butyl, isobutyl or tertiary-butyl), more preferably methyl.
As used herein, the term xe2x80x9carylxe2x80x9d means an aromatic group, such as phenyl or naphthyl, or a heteroaromatic group containing one or more heteroatom, such as pyridyl, pyrrolyl quinolinyl furanyl, thienyl, oxadiazolyl, thiadiazolyl, thiazolyl, oxazolyl isoxazolyl pyrazolyl, triazolyl, imidazolyl or pyrimidinyl.
As used herein, the term xe2x80x9calkoxyxe2x80x9d means alkyl-Oxe2x80x94. As used herein, the term xe2x80x9clower alkoxyxe2x80x9d means loweralkyl-Oxe2x80x94. As used herein, the term xe2x80x9caryloxyxe2x80x9d means aryl-Oxe2x80x94.
As used herein, the term xe2x80x9chalogenxe2x80x9d means a fluorine, chlorine, bromine or iodine radical, preferably a fluorine or chlorine radical.
As used herein the term xe2x80x9cprodrugxe2x80x9d means any pharmaceutically acceptable prodrug of the compound of formula (I) which is metabolised in vivo to a compound of formula (I).
As used herein, the term xe2x80x9cpharmaceutically acceptable saltxe2x80x9d means any pharmaceutically acceptable salt of the compound of formula (I). Salts may be prepared from pharmaceutically acceptable non-toxic acids and bases including inorganic and organic acids and bases. Such acids include acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, dichloroacetic, ethanesulfonic, formic, fumaric, gluconic, glutamic, hippuric, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, oxalic, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, oxalic, p-toluenesulfonic and the like. Particularly preferred are fumaric, hydrochloric, hydrobromic, phosphoric, succinic, sulfuric and methanesulfonic acids, particularly fumaric acid. Acceptable base salts include alkali metal (e.g sodium, potassium), alkaline earth metal (e.g. calcium, magnesium) and aluminium salts.
As used herein, the term xe2x80x9caddition compoundxe2x80x9d means any pharmaceutically acceptable addition compound of the compound of formula (I). Addition compounds include those which are formed without change of valency from the union between a compound of formula (I) and one or more other molecules, particularly solvates, hydrates and inclusion complexes (such as cyclodextrin complexes).
As used herein, the term xe2x80x9cA is a 5- or 6-membered ringxe2x80x9d refers to a ring containing 5 or 6 ring atoms in total, i.e. including the carbon atoms in the unsaturated positions of the indole ring to which A is fused.
As used herein, the term xe2x80x9ccarbocyclic ringxe2x80x9d refers to a ring wherein all the ring atoms are carbon atoms.
As used herein, the term xe2x80x9cpartially unsaturated ringxe2x80x9d refers to a ring which contains unsaturated ring atoms and one or more double bonds but which is not aromatic, for example a cyclohexenyl, cyclopentenyl, or thiacyclohexenyl ring. It will be appreciated therefore that a partially unsaturated ring A may contain one double bond, i.e. the double bond between the unsaturated 2 and 3 positions of the indole ring to which the ring A is fused, in which case the atoms of the ring A, other than the carbon atoms in the unsaturated 2 and 3 positions of the indole ring to which A is fused, are saturated. Alternatively, a partially unsaturated ring A may contain an additional double bond provided that this additional double bond does not result in the ring A being aromatic.
Where any of R1 to R7 is an alkyl group or an alkyl-containing group (such as alkoxy, alkylamino or alkylthio, for instance) as defined in formula (I) above, then that alkyl group, or the alkyl group of the alkyl-containing group, may be substituted or unsubstituted. Where any of R4 to R7 is an aryl group or an aryl-containing group (such as aryloxy, for instance) as defined in formula (I), then said aryl group, or the aryl group of the aryl-containing group, may be substituted or unsubstituted. The ring A may be substituted or unsubstituted, preferably unsubstituted. Where any of R1 to R7 or A is substituted, there will generally be 1 to 3 substituents present, preferably 1 substituent Substituents may include:
carbon-containing groups such as
alkyl,
aryl (e.g. substituted and unsubstituted phenyl),
arylalkyl; (e.g. substituted and unsubstituted benzyl);
halogen atoms and halogen containing groups such as
haloalkyl (e.g. trifluoromethyl),
haloaryl (e.g. chlorophenyl);
oxygen containing groups such as
oxo,
alcohols (e.g. hydroxy, hydroxyalkyl, hydroxyaryl, (aryl)(hydroxy)alkyl),
ethers (e.g. alkoxy, aryloxy, alkoxyalkyl, aryloxyalkyl, alkoxyaryl, aryloxyaryl),
aldehydes (e.g. carboxaldehyde),
ketones (e.g. alkylcarbonyl, arylcarbonyl, alkylcarbonylalkyl, alkylcarbonylaryl, arylcarbonylalkyl, arylcarbonylaryl, arylalkylcarbonyl, arylalkylcarbonylalkyl, arylalkylcarbonylaryl)
acids (e.g. carboxy, carboxyalkyl, carboxyaryl),
acid derivatives such as esters
(e.g. alkoxycarbonyl, aryloxycarbonyl, alkoxycarbonylalkyl, aryloxycarbonylalkyl, alkoxycarbonylaryl, aryloxycarbonylaryl, alkylcarbonyloxy, alkylcarbonyloxyalkyl), amides
(e.g. aminocarbonyl, mono- or di-alkylaminocarbonyl, aminocarbonylalkyl, mono- or di-alkylcarbonylalkyl, arylaminocarbonyl or arylalkylaminocarbonyl, alkylcarbonylamino, arylcarbonylamino or arylalkylcarbonyl amino), carbamates
(eg. alkoxycarbonylamino, aryloxycarbonylamino, arylalkyloxycarbonylamino, aminocabonyloxy, mono- or di-alkylaminocarbonyloxy, arylaminocarbonyloxy or arylalkylaminocarbonyloxy) and ureas
(eg. mono- or di-alkylaminocarbonylamino, arylaminocarbonylamino or aryalkylaminocarbonylamino);
nitrogen containing groups such as
amines (e.g. amino, mono- or dialkylamino, arylamino, aminoalkyl, mono- or dialkylaminoalkyl),
azides,
nitriles (e.g. cyano, cyanoalkyl),
nitro;
sulfur containing groups such as
thiols, thioethers, sulfoxides, and sulfones
(e.g. alkylthio, alkylsulfinyl, alkylsulfonyl, alkylthioalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, arylthio, arylsulfinyl, arylsulfonyl, alkylthioalkyl, arylsulfinylalkyl, arylsulfonylalkyl)
and heterocyclic groups containing one or more, preferably one, heteroatom,
(e.g. thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, oxadiazolyl, thiadiazolyl, aziridinyl, azetidinyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, tetrahydrofuranyl, pyranyl, pyronyl, pyridyl, pyrazinyl, pyridazinyl, piperidyl, hexahydroazepinyl, piperazinyl, morpholinyl, thianaphthyl, benzofuranyl, isobenzofuranyl, indolyl, oxyindolyl, isoindolyl, indazolyl, indolinyl 7-azaindolyl, benzopyranyl, coumarinyl, isocoumarinyl, quinolinyl, isoquinolinyl, naphthridinyl, cinnolinyl quinazolinyl, pyridopyridyl, benzoxazinyl, quinoxalinyl, chromenyl, chromanyl, isochromanyl, phthalazinyl, and carbolinyl).
It is preferred that the compounds of formula (I) are selected from those wherein R1 to R7 and A are as defined above with the proviso that if A is a 5- or 6-membered partially unsaturated carbocyclic ring then at least one of R4 to R7 is other than hydrogen.
In the compounds of formula (I), preferably R1 and R2 are independently selected from hydrogen and lower alkyl (preferably acyclic lower alkyl and more preferably methyl), and preferably from hydrogen.
In one embodiment, the compounds of formula (I) are selected from compounds in which R1 is the same as R2. Preferably, R1 and R2 are both hydrogen.
The compounds of formula (I) are preferably selected from compounds in which R3 is lower alkyl, preferably acyclic lower alkyl, and more preferably methyl.
R5 is selected from hydrogen, halogen, hydroxy, alkyl (including cycloalkyl, halo-alkyl (such as trifluoromethyl) and arylalkyl), aryl, amino, alkylamino, dialkylamino, alkoxy (including arylalkoxy), aryloxy, alkylthio, alkylsulfoxyl, alkylsulfonyl, nitro, carbonitrile, carbo-alkoxy, carbo-aryloxy and carboxyl.
In one embodiment, Rs is selected from halogen, hydroxy, alkyl (including cycloalkyl, halo-alkyl (such as trifluoromethyl) and arylalkyl), aryl, amino, alkylamino, dialkylamino, alkoxy (including arylalkoxy), aryloxy, alkylthio, alkylsulfoxyl, alkylsulfonyl, nitro, carbonitrile, carbo-alkoxy, carbo-aryloxy and carboxyl.
Preferably R5 is selected from hydrogen, halogen and alkoxy, preferably from alkoxy and halogen, and preferably from alkoxy. Where R5 is halogen, it is preferred that R5 is selected from fluoro, chloro and bromo, preferably from fluoro and chloro and more preferably from fluoro. Where R5 is selected from alkoxy, it is preferred that R5 is selected from lower alkoxy, preferably acyclic lower alkoxy.
R4, R6 and R7 are independently selected from hydrogen, halogen, hydroxy, alkyl (including cycloalkyl halo-alkyl (such as trifluoromethyl) and arylalkyl), aryl amino, alkylamino, dialkylamino, alkoxy (including arylalkoxy), aryloxy, alkylthio, alkylsulfoxyl, alkylsulfonyl, nitro, carbonitrile, carbo-alkoxy, carbo-aryloxy and carboxyl.
Preferably R4 is selected from hydrogen, halogen, alkyl and alkoxy, and is preferably hydrogen Where R4 is alkyl, it is preferred that R4 is lower alkyl, preferably acyclic lower alkyl. Where R4 is alkoxy, it is preferred that R4 is lower alkoxy, preferably acyclic lower alkoxy.
Preferably R6 is selected from hydrogen and halogen. Where R6 is selected from halogen, R6 is preferably fluoro or chloro, preferably fluoro.
Preferably R7 is selected from hydrogen, halogen and alkoxy, preferably from hydrogen and halogen, and preferably from halogen. Where R7 is alkoxy, it is preferred that R7 is lower alkoxy, preferably acyclic lower alkoxy. Where R7 is halogen, it is preferred that R7 is selected from fluoro, chloro and bromo, preferably from chloro and bromo and preferably chloro.
It is preferred that at least one of R4 to R7 is a group other than hydrogen
Where A is a heterocyclic ring, A may contain one or more heteroatom(s), and preferably only one heteroatom. Where A contains one or more heteroatom(s), it is preferred that the heteroatoms are selected from N, O and S. Where A is partially unsaturated, it is preferred that A contains no heteroatoms.
It is preferred that A is a 5-membered ring.
It is preferred that A is partially unsaturated, preferably wherein the atoms of the ring A, other than the carbon atoms in the unsaturated 2 and 3 positions of the indole ring to which the ring A is fused, are saturated.
In one embodiment, the compounds of formula (I) are selected from compounds wherein A is a 5-membered partially unsaturated carbocyclic ring, a 5-membered heterocyclic ring (preferably aromatic) or a 6membered partially unsaturated carbocyclic ring, preferably from compounds wherein A is a 5-membered partially u rated carbocyclic ring or a 5-membered heterocyclic ring, and more preferably from compounds wherein A is a 5-membered partially unsaturated carbocyclic ring.
In a further embodiment, the compounds of formula (I) are selected from compounds wherein A is selected from the group consisting of cyclopentenyl (including oxocyclopentenyl (particularly 1-oxocyclopent-4-enyl)), cyclohexenyl, thiacyclohexenyl (particularly 4-thiacyclohexenyl) and thienyl.
The compounds of the invention may contain one or more asymmetric carbon atoms, so that the compounds can exist in different stereoisomeric forms. The compounds can be, for example, racemates or optically active forms. The optically active forms can be obtained by resolution of the racemates or by asymmetric synthesis. In a preferred embodiment of the invention, where all of R4 to R7 are hydrogen, the preferred stereochemistry at the carbon atom to which R3 and NR1R2 are bound is (R). In an alternative embodiment, where R5 or R7 is a group other than hydrogen, the preferred stereochemistry at the carbon atom to which R3 and NR1R2 are bound is (S).
In one embodiment of the invention, the compounds of formula (I) are preferably selected from:
(S)-1-(7,8-difluoro-1,2,3,4-tetrahydrocyclopent[b]indol-4-yl)-2-propylamine,
(S)-1-(7-fluoro-1,2,3,4-tetrahydrocyclopent[b]indol-4-yl)-2-propylamine,
(S)-1-(8-chloro-1,2,3,4-tetrahydrocyclopent[b]indol-4-yl)-2-propylamine,
(S)-1-(6-methoxy-1,2,3,4-tetrahydrocyclopent[b]indol-4-yl)-2-propylamine,
(S)-1-(7-fluoro-6-methoxy-1,2,3,4-tetrahydrocyclopent[b]indol-4-yl)-2-propylamine,
(S)-1-(7-fluoro-8-methoxy-1,2,3,4-tetrahydrocyclopent[b]indol-4yl)-2-propylamine,
(S)-1-(8-chloro-7-fluoro-1,2,3,4-tetrahydrocyclopent[b]indol-4-yl)-2-propylamine,
(S)-1-(1,2,3,4-tetrahydrocyclopent[b]indol-4-yl)-2-propylamine and
(R)-1-(1,2,3,4-tetrahydrocyclopent[b]indol-4-yl)-2-propylamine.
According to a further aspect of the invention, there is provided a compound of formula (I) for use in therapy.
The compounds of formula (I) may be used in the treatment (including prophylactic treatment) of disorders associated with 5-HT2 receptor function. The compounds may act as receptor agonists or antagonists, preferably receptor agonists. Preferably, the compounds may be used in the treatment (including prophylactic treatment) of disorders associated with 5-HT2B and 5-HT2C receptor function. Preferably, the compounds may be used in the treatment (including prophylactic treatment) of disorders where 5-HT2C receptor activity is required, and preferably where a 5HT2C receptor agonist is required.
The compounds of formula (I) may be used in the treatment or prevention of central nervous disorders such as depression, atypical depression, bipolar disorders, anxiety disorders, obsessive-compulsive disorders, social phobias or panic states, sleep disorders, sexual dysfunction, psychoses, schizophrenia, migraine and other conditions associated with cephalic pain or other pain, raised intracranial pressure, personality disorders, age-related behavioural disorders, behavioural disorders associated with dementia, organic mental disorders, mental disorders in childhood, aggressivity, age-related memory disorders, chronic fatigue syndrome, drug and alcohol addiction, obesity, bulimia, anorexia nervosa or premenstrual tension; damage of the central nervous system such as by trauma stroke, neurodegenerative diseases or toxic or infective CNS diseases such as encephalitis or meningitis; cardiovascular disorders such as thrombosis; gastrointestinal disorders such as dysfunction of gastrointestinal motility; diabetes insipidus; and sleep apnea.
According to a further aspect of the invention, there is provided use of a compound of formula (I) in the manufacture of a medicament for the treatment (including prophylaxis) of the above-mentioned disorders. In a preferred embodiment, there is provided use of a compound of formula (I) in the manufacture of a medicament for the treatment (including prophylaxis) of obesity.
According to a further aspect of the invention, there is provided a method of treating a disorder selected from the group consisting of the above-mentioned disorders comprising administering to a patient in need of such treatment an effective dose of a compound of formula (I). In a preferred embodiment, there is provided a method of treatment (including prophylaxis) of obesity.
According to a further aspect of the invention, there is provided a pharmaceutical composition comprising a compound of formula (I) in combination with a pharmaceutically acceptable carrier or excipient and a method of making such a composition comprising combining a compound of formula (I) with a pharmaceutically acceptable carrier or excipient.
According to a further aspect of the invention, there is provided a method of preparing a compound of formula (I), for instance in the manner described below in the Reaction Schemes. R1 to R7 are as previously defined.
As used herein, the term xe2x80x9csaturated 2,3-ring-fused indolesxe2x80x9d refers to a tricyclic compound having a ring A as defined herein which is fused to an indole ring across the double bond in the 2- and 3-positions of the indole ring, wherein the atoms of the ring A, other than the carbon atoms in the unsaturated 2- and 3-positions of the indole ring to which A is fused, are saturated.
As used herein, the term xe2x80x9cunsaturated 2,3-ring-fused indolesxe2x80x9d refers to a tricyclic compound having a ring A as defined herein which is fused to an indole ring across the double bond in the 2- and 3-positions of the indole ring, wherein one or more of the atoms of the ring A, other than the carbon atoms in the unsaturated 2- and 3-positions of the indole ring to which A is fused, are unsaturated. It will be understood that the term xe2x80x9cunsaturated 2,3-ring-fused indolesxe2x80x9d includes compounds wherein the ring A is aromatic.
In Reaction Scheme 1, the saturated 2,3-ring-fused indoles (IV) may be formed by sequential reaction of the suitably substituted N-2-bromophenyl acetamide (eg R=CF3) (II) with methyllithium and the appropriate 2-halo-cyclic ketone (III), followed by tert butyllithium and then trifluoroacetic acid. The N-alkyl ring-fused indole (V) (eg R=tert Bu) may then be obtained by reaction of (IV) with an appropriate carbamylethylsulfonate in the presence of a strong base such as potassium hydroxide in a solvent such as methyl sulfoxide. The indole (I) (R1=R2=H) may then be obtained by reaction of the indole (V) with a reagent suitable to reveal the protected amine function. 
The compounds of formula (I) (R1 and/or R2 alkyl) may be prepared from compounds of formula (I) (R1=R2=H) by standard methods such as reductive alkylation with an appropriate aldehyde or ketone in the presence of a reducing agent such as sodium triacetoxyborohydride, formic acid or sodium cyanoborohydride.
The unsaturated 2,3-ring-fused indoles (I) may be formed in a similar manner to the saturated 2,3-ring-fused indoles (I), through the intermediacy of the unsaturated 2,3-ring-fused indole (IV) obtained from the saturated 2,3-ring-fused indole (IV) under standard dehyrogenation conditions such as through treatment with DDQ or Pd on carbon in a suitable solvent such as dioxan and xylene respectively.
Alternatively, compounds of the invention can be conveniently prepared according to Reaction Scheme 2. Treatment of phenylhydrazine (II) with a cyclic ketone under the acidic conditions in a suitable solvent, such as ethanol or water, produces indole (III). Reaction of indole (III) with an alkylating agent such as tert-butyl [2-[(1-methanesulfonyl)oxy]propyl]carbamate in the presence of a base such as potassium hydroxide in a suitable solvent e.g. methyl sulfoxide gives indolecarbamate (IV). A compound of formula (I) where R1=R2=H can be prepared by treatment of (IV) with an acid such as hydrochloric acid in a suitable solvent such as methanol or by use of a strong base such as potassium tert-butoxide in a solvent such as methyl sulfoxide. A compound of formula (I) where R1 and/or R2=alkyl can be prepared by reductive alkylation using an aldehyde or ketone in the presence of a reducing agent such as formic acid, sodium cyanoborohydride or sodium triacetoxyborohydride. 
If, in any of the other processes mentioned herein, the substituent groups R1, R2, R3, R4, R5, R6 or R7 is other than the one required, the substituent group may be converted to the desired substituent by known methods. The substituents R1, R2, R3, R4, R5, R6 or R7 may also need protecting against the conditions under which the reaction is carried out. In such a case, the protecting group may be removed after the reaction has been completed.
The processes described above may be carried out to give a compound of the invention in the form of a free base or as an acid addition salt. If the compound of the invention is obtained as an acid addition salt, the free base can be obtained by basifying a solution of the acid addition salt. Conversely, if the product of the process is a free base, an acid addition salt may be obtained by dissolving the free base in a suitable organic solvent and treating the solution with an acid, in accordance with conventional procedures for preparing acid addition salts from basic compounds.
The compositions of the present invention may be formulated in a conventional manner using one or more pharmaceutically acceptable carriers. Thus, the active compounds of the invention may be formulated for oral, buccal, intranasal, parenteral (e.g., intravenous, intramuscular or subcutaneous) transdermal or rectal administration or in a form suitable for administration by inhalation or insufflation.
For oral administration, the pharmaceutical compositions may take the form of, for example, tablets or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (e.g. pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropylnethylcellulose); fillers (e.g. lactose, microcrystalline cellulose or calcium phosphate); lubricants (e.g. magnesium stearate, talc or silica); disintegrants (e.g. potato starch or sodium starch glycollate); or wetting agents (e.g. sodium lauryl sulfate). The tablets may be coated by methods well known in the art. Liquid preparations for oral administration may take the form of, for example, solutions, syrups or suspensions, or they may be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents (e.g. sorbitol syrup, methyl cellulose or hydrogenated edible fats); emulsifying agents (e.g. lecithin or acacia); non-aqueous vehicles (e.g. almond oil, oily esters or ethyl alcohol); and preservatives (e.g. methyl or propyl p-hydroxybenzoates or sorbic acid).
For buccal administration the composition may take the form of tablets or lozenges formulated in conventional manner.
The active compounds of the invention may be formulated for parenteral administration by injection, including using conventional catheterization techniques or infusion. Formulations for injection may be presented in unit dosage form e.g. in ampoules or in multi-dose containers, with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulating agents such as suspending, stabilising and/or dispersing agents.
Alternatively, the active ingredient may be in powder form for reconstitution with a suitable vehicle, e.g. sterile pyrogen-free water, before use.
The active compounds of the invention may also be formulated in rectal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter or other glycerides.
For intranasal administration or administration by inhalation, the active compounds of the invention are conveniently delivered in the form of a solution or suspension from a pump spray container that is squeezed or pumped by the patient or as an aerosol spray presentation from a pressurized container or a nebulizer, with the use of a suitable propellant, e.g. dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressured aerosol, the dosage unit may be determined by providing a valve to deliver a metered amount. The pressurized container or nebulizer may contain a solution or suspension of the active compound. Capsules and cartridges (made, for example, from gelatin) for use in an inhaler or isufflator may be formulated containing a powder mix of a compound of the invention and a suitable powder base such as lactose or starch.
A proposed dose of the active compounds of the invention for oral parenteral or buccal administration to the average adult human for the treatment of the conditions referred to above (e.g., obesity) is 0.1 to 500 mg of the active ingredient per unit dose which could be administered, for example, 1 to 4 times per day.
The invention will now be described in detail with reference to the following examples. It will be appreciated that the invention is described by way of example only and modification of detail may be made without departing from the scope of the invention.
Assay Procedures
1. Binding to Serotonin Receptors
The binding of compounds of formula (I) to serotonin receptors was determined in vitro by standard methods. The preparations were investigated in accordance with the assays given hereinafter.
Method (a): For the binding to the 5-HT2C receptor the 5-HT2C receptors were radiolabelled with [3H]-5-HT. The affinity of the compounds for 5-HT2C receptors in a CHO cell line was determined according to the procedure of D. Hoyer, G. Engel and H.O. Kalkman, European J. Pharmacol., 1985, 118, 13-23.
Method (b): For the binding to the 5-HT2B receptor the 5-HT2B receptors were radiolabelled with [3H]-5-HT. The affinity of the compounds for human 5-HT2B receptors in a CHO cell line was determined according to the procedure of K. Schmuck, C. Ullmer, P. Engels and H. Lubbert, FEBS Lett., 1994, 342, 85-90.
Method (c): For the binding to the 5-HT2A receptor the 5-HT2A receptors were radiolabelled with [125I]-DOI. The affinity of the compounds for 5-HT2A receptors in a CHO cell line was determined according to the procedure of D. J. McKenna and S. J. Peroutka, J. Neurosci., 1989, 9/10, 3482-90.
The thus determined activity of compounds of formula (I) is shown in Table 1.
2. Functional Activity
The functional activity of compounds of formula (I) was assayed using a Fluorimetric Imaging Plate reader (FLIPR) in the following manner.
CHO cells expressing either the h5-HT2C or h5-HT2A receptors were counted and plated into standard 96 well microtitre plates before the day of testing to give a confluent monolayer. The following day the cells were dye loaded with the calcium sensitive dye Fluo 3-AM by incubation with serum free culture maintenance media containing pluronic acid and Fluo 3-AM dissolved in DMSO at 37xc2x0 C. in a CO2 incubator at 95% humidity for approximately 90 minutes. Unincorporated dye was removed by washing with Hanks balanced salt solution containing 20 mM HEPES and 2.5 mM probenecid (the assay buffer) using an automated cell washer to leave a total volume of 100 xcexcL/well.
The drug (dissolved in 50 xcexcL of assay buffer) was added at a rate of 70 xcexcL/sec to each well of the FLIPR 96 well plate during fluorescence measurements. The measurements are taken at 1 sec intervals and the maximum fluorescent signal was measured (approx 10-15 secs after drug addition) and compared with the response produced by 10 xcexcM 5-HT (defined as 100%) to which it is expressed as a percentage response (relative efficacy). Dose response curves were constructed using Graphpad Prism (Graph Software Inc.).
The thus determined activity of compounds of formula (I) is shown in Table 2.